A fundamental aspect of the human aging process is the cellular and organ-based decline in regenerative potential. This decline involves the failure of the normal process of tissue homeostasis. There is increasing evidence that the accumulation of DNA damage in stem cells, coupled with molecular changes in the tissue niche, is partially responsible for the loss of regeneration and subsequent aging in mammalian organisms. The exact mechanism of normal tissue homeostasis and its failure, however, still remain unclear. Our project is focused on elucidating both stem cell-intrinsic and niche-based changes that lead to aging. ATR is a protein kinase that is essential for preserving genomic integrity during DNA replication. Perturbation of its function leads to genomic instability and eventual cell death. This cell death causes a rapid turnover of remaining cells in a tissue, leading to accelerated aging. Thus, by deleting ATR in specific cells, we can model tissue regeneration, and the eventual failure of regeneration that leads to premature aging. Additionally, the loss of ATR in the context of an apoptosis-incompetent cell causes the initiation of a secretory program which involves factors that are unique to this system, and not identified in the panel of senescence-associated secretory protein (SASP) factors. We hypothesize that it is the secretion of these factors that prevents tissue regeneration in mice with loss of ATR in a p53-null background, and that modulation of this secretory panel will improve tissue regeneration. Thus, the studies described in this proposal aim to uncover natural mechanisms of aging, as well as to find ways to alter these mechanisms in order to improve the aging process.